EP3603660B1 - Langwirkender mutanter humaner fibroblast-wachstumsfaktor 21 zur behandlung von nichtalkoholischer steatohepatitis - Google Patents

Langwirkender mutanter humaner fibroblast-wachstumsfaktor 21 zur behandlung von nichtalkoholischer steatohepatitis Download PDF

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EP3603660B1
EP3603660B1 EP18771156.9A EP18771156A EP3603660B1 EP 3603660 B1 EP3603660 B1 EP 3603660B1 EP 18771156 A EP18771156 A EP 18771156A EP 3603660 B1 EP3603660 B1 EP 3603660B1
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growth factor
fibroblast growth
recombinant human
nash
mouse chimeric
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EP3603660A1 (de
EP3603660A4 (de
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Jian Li
Jun Han
Xiaohui Ma
Ping TAI
Genbei Wang
Xiaodan CAO
Ruijing HUANG
Yongjie Jin
Jing Li
Chen Chen
Guoyong JIA
Yuanyuan Wang
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Tasly Pharmaceutical Group Co Ltd
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Tasly Biopharmaceuticals Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/50—Fibroblast growth factor [FGF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1825—Fibroblast growth factor [FGF]

Definitions

  • the present disclosure relates to the field of biomedicine, and particularly relates to the use of a PEGylated Recombinant Human-mouse Chimeric Fibroblast Growth Factor 21 in the preparation of drugs for treating non-alcoholic steatohepatitis.
  • Non-alcoholic fatty liver disease also known as non-alcoholic fatty liver
  • NAFLD alcoholic liver disease
  • ALD alcoholic liver disease
  • NAFLD and NASH have become the leading causes of liver disease in Western countries in the past 20 years. Without timely control, NAFLD can easily progress to NASH as fat continues to accumulate excessively. In addition to excessive accumulation of fat, NASH differs from NAFLD in the presence of inflammatory cell infiltration in liver, the degree of hepatic fibrosis, and the degree of liver cell damage. Furthermore, if NASH continues to progress without effective control, it is highly likely to cause hepatic fibrosis, cirrhosis and even liver cancer.
  • Fibroblast growth factor-21 (FGF-21) is another metabolic regulator recently discovered in vivo. It belongs to FGF family and specifically acts on liver, fat, and islet cells. FGF-21 can effectively and safely regulate blood glucose and blood fat independently of insulin, which has got researchers' a lot of attention. It has also been reported that FGF-21 can effectively prevent and treat NAFLD induced in vitro ( Liu Min et al., Effect of fibroblast growth factor-21 on lipid metabolism of non-alcoholic fatty liver cell model induced in vitro. Journal of Jilin University, May 2012, Vol. 38, No.
  • CN2013101152100 Publication Number: CN103193878A ; Applicant: Harbin Boao Biomedical Technology Development Co., Ltd. discloses a new long-acting mutant human FGF and the polyethylene glycol (PEG) conjugate thereof.
  • the protein structure of the said FGF-PEG conjugate is shown in Sequence 3 and its preparation method is shown in Example 4.
  • This conjugate was later named by its inventors as PEGylated Recombinant Human-mouse Chimeric Fibroblast Growth Factor 21 (or PEG-hmFGF21 for short).
  • PEGylated Recombinant Human-mouse Chimeric Fibroblast Growth Factor 21 has the functions of regulating blood glucose, lowering blood triglycerides, and regulating total cholesterol, et al.. However, there have been no reports of PEGylated Recombinant Human-mouse Chimeric Fibroblast Growth Factor 21 in the treatment of NASH so far.
  • the PEGylated Recombinant Human-mouse Chimeric Fibroblast Growth Factor 21 has the amino acid sequence set forth in Sequence 3 disclosed in the patent application CN2013101152100 (Publication Number: CN103193878A ) and is obtainable according to the preparation method disclosed in Example 4 of CN2013101152100 (Publication Number: CN103193878A ).
  • PEGylated Recombinant Human-mouse Chimeric Fibroblast Growth Factor 21 or its salt can lower the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum, improve steatosis and lobular inflammation, reduce the degree of hepatocellular ballooning degeneration, and improve liver damage.
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • the NASH includes, not limited to, hepatitis-induced NASH, obesity-induced NASH, diabetes-induced NASH, insulin resistance-induced NASH, hypertriglyceridemia-induced NASH, abetalipoproteinemia-induced NASH, NASH induced by glycogen storage disease, NASH induced by Wake's Disease, NASH induced by Wolman disease, and lipodystrophia-induced NASH, et al..
  • the drugs mean pharmaceutical compositions containing PEGylated Recombinant Human-mouse Chimeric Fibroblast Growth Factor 21 or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient.
  • the pharmaceutical compositions can be prepared into any pharmaceutically acceptable dosage form, including tablets, capsules, granules, pills, powders, paste, sublimed preparation, dustpowders, solutions, injections, suppositories, sprays, drops, patches, and drop pills.
  • Drugs of the present disclosure are preferably prepared into injectable drugs, such as powder injections or liquid injections.
  • the liquid injections include water injections, organic solvent injections, and suspension injections, et al..
  • the preparations of the pharmaceutical compositions for oral administration may contain conventional excipients such as the bonding agent, stuffing bulking agent, diluting agent, tablet compressing agent, lubricating agent, disintegrating agent, coloring agent, flavoring agent, and wetting agent.
  • the suitable stuffing bulking agents include starch, sucrose, cellulose, mannitol, lactose, and other similar ones.
  • the suitable disintegrating agents include starch, polyvinyl pyrrolidone and starch derivatives such as sodium starch glycolate.
  • the suitable lubricating agents include, for example, magnesium stearate.
  • the solid form of the compositions for oral administration can be prepared through conventional methods including mixing, filling, tablet compressing, et al..
  • the excipients commonly-used include mannitol, sorbitol, sodium pyrosulfite, sodium hydrogen sulfite, sodium thiosulfate, cysteine hydrochloride, thioglycolic acid, methionine, vitamin C, disodium EDTA, calcium disodium edetate, carbonates of alkali metal and aqueous solutions thereof, acetates of alkali metal and aqueous solutions thereof, phosphates of alkali metal and aqueous solutions thereof, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acid, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, D- mannitol, silicon derivatives, cellulose and
  • the usage and dosage of the pharmaceutical composition of the present disclosure are determined according to conditions of diseases while being used.
  • the pharmaceutical composition can be administered 1-6 times a day for 1-10 doses each, and each dose can be 0.1 mg-1000 mg.
  • PEGylated Recombinant Human-mouse Chimeric Fibroblast Growth Factor 21 has the following advantages: PEGylated Recombinant Human-mouse Chimeric Fibroblast Growth Factor 21 can significantly lower the levels of ALT and AST in serum, improve steatosis and lobular inflammation, reduce the degree of hepatocellular ballooning degeneration, and improve the pathological score of liver damage. The final results demonstrate that the present invention can be used to treat NASH with superior effectiveness to prior art.
  • a mouse model of MCD diet-induced NASH is used in this experiment, mainly because this diet has been used for more than 40 years and its production process has become more mature.
  • the characterization this diet induced has obtained multiple verification in terms of its rapidity (i.e. NASH related symptoms can be triggered in about 4 weeks) and effectiveness (i.e. symptoms induced have great similarity to those of human NASH).
  • mice of eight-week-old were began to be fed MCD diet.
  • MCD diet fed for two weeks the mice were randomly divided into 4 groups according to the body weight: a solvent group, a FGF-21 group, a low-dose PEGylated Recombinant Human-mouse Chimeric Fibroblast Growth Factor 21 group, and a high-dose PEGylated Recombinant Human-mouse Chimeric Fibroblast Growth Factor 21 group. There were 10 mice in each group and they were administered once a day via hypodermic injection for two weeks.
  • Table 1 Details of animal grouping and administration are shown in Table 1: Table 1: Animal grouping and administration Group n Dose Administration period (day) Solvent group 10 Solvent in the same volume 14d FGF-21 group 10 0.4mg/kg/d 14d Low-dose PEGylated Recombinant Human-mouse Chimeric Fibroblast Growth Factor 21 group 10 0.125mg/kg/d 14d High-dose PEGylated Recombinant Human-mouse Chimeric Fibroblast Growth Factor 21 10 2mg/kg/d 14d group
  • mice After the administration, the mice were killed and their relevant tissues were removed for subsequent analyses.
  • ALT and AST in serum were determined using a clinically general assay kit (provided by Shanghai Shensuo-UNF Medical. Diagnostic Articles Co.,Ltd ).
  • liver sections were stained with hematoxylin-eosin, and finally the morphology of liver tissue of each mouse was observed under a microscope.
  • the collagen deposition in mouse liver was observed through Sirius Red (SR) staining method.
  • the specific steps were as follows: The liver sections from paraffin blocks were stained using the Sirius Red staining kit, and finally the fibrosis of liver tissue of each mouse was observed under a microscope.
  • NASH Clinical Research Network Scores mainly including three aspects: steatosis, lobular inflammation, and ballooning degeneration.
  • mice were randomly selected from each group, and five microscopic fields of view within the H&E stained liver tissue sections of the corresponding mouse were randomly selected based on which a score is given from the above three aspects, objectively evaluating the degree of hepatitis of mice in each group.
  • SPSS16.0 statistical software was used for statistics and data analysis. A t-test was used to compare the difference between two groups of data. One-way ANOVA test and multiple linear regression analysis were used to compare differences among multiple groups of data. The difference was statistically significant with P ⁇ 0.05.
  • PEGylated Recombinant Human-mouse Chimeric Fibroblast Growth Factor 21 not only has the efficacy of improving lobular inflammation, ballooning, and NASH total scores but also its efficacy herein is better than FGF-21.
  • Detections after injection of PEGylated Recombinant Human-mouse Chimeric Fibroblast Growth Factor 21 show that compared with the solvent group and FGF-21 group, low-dose PEGylated Recombinant Human-mouse Chimeric Fibroblast Growth Factor 21 group and/or high-dose PEGylated Recombinant Human-mouse Chimeric Fibroblast Growth Factor 21 group can significantly lower the levels of ALT and AST in serum, improve steatosis and lobular inflammation, reduce the degree of hepatocellular ballooning degeneration, and improve the pathological score of liver damage. These results indicate that PEGylated Recombinant Human-mouse Chimeric Fibroblast Growth Factor 21 has the effect of treating NASH.
  • PEGylated Recombinant Human-mouse Chimeric Fibroblast Growth Factor 21 has the clinical application value in the treatment of NASH which is superior to the prior art.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biophysics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Toxicology (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Immunology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (8)

  1. PEGylierter rekombinanter chimärer Human-Maus-Fibroblast-Wachstumsfaktor 21 oder pharmazeutisch annehmbares Salz davon zur Verwendung beim Behandeln von nichtalkoholischer Steatohepatitis, wobei der PEGylierte rekombinante chimäre Human-Maus-Fibroblast-Wachstumsfaktor 21 durch Bereitstellen eines Peptids erhältlich ist, das aus der folgenden Aminosäuresequenz besteht:
    Figure imgb0002
    und PEGylieren des Peptids bei pH-Wert 6 unter Verwendung von mPEG-ALD mit einem Molekulargewicht von 20 kD und Natriumcyanoborhydrid.
  2. PEGylierter rekombinanter chimärer Human-Maus-Fibroblast-Wachstumsfaktor 21 oder pharmazeutisch annehmbares Salz davon zur Verwendung nach Anspruch 1, wobei die Verwendung aus einer Verringerung der Konzentrationen von Alanin-Aminotransferase und Aspartat-Aminotransferase in Serum, Verbessern von Steatose und lobulärer Entzündung, Verringern des Grads an hepatozellulärer ballonierender Degeneration und Verbessern von Leberschäden ausgewählt ist.
  3. PEGylierter rekombinanter chimärer Human-Maus-Fibroblast-Wachstumsfaktor 21 oder pharmazeutisch annehmbares Salz davon zur Verwendung nach Anspruch 1, wobei die nichtalkoholische Steatohepatitis (NASH) aus Hepatitis-induzierter NASH, Adipositasinduzierter NASH, Diabetes-induzierter NASH, Insulinresistenz-induzierter NASH, Hypertriglyceridämie-induzierter NASH, Abetalipoproteinämie-induzierter NASH, NASH, die durch Glykogenspeicherkrankheit induziert ist, NASH, die durch Wake-Krankheit induziert ist, NASH, die durch Wolman-Krankheit induziert ist oder Lipodystrophieinduzierter NASH ausgewählt ist.
  4. PEGylierter rekombinanter chimärer Human-Maus-Fibroblast-Wachstumsfaktor 21 oder pharmazeutisch annehmbares Salz davon zur Verwendung nach Anspruch 1, wobei die Arzneimittel pharmazeutische Zusammensetzungen sind, die PEGylierten rekombinanten chimären Human-Maus-Fibroblast-Wachstumsfaktor 21 oder ein pharmazeutisch annehmbares Salz davon als aktiven pharmazeutischen Wirkstoff enthalten.
  5. PEGylierter rekombinanter chimärer Human-Maus-Fibroblast-Wachstumsfaktor 21 oder pharmazeutisch annehmbares Salz davon zur Verwendung nach Anspruch 4, wobei die pharmazeutischen Zusammensetzungen in einer beliebigen pharmazeutisch annehmbaren Darreichungsform hergestellt sein können.
  6. PEGylierter rekombinanter chimärer Human-Maus-Fibroblast-Wachstumsfaktor 21 oder pharmazeutisch annehmbares Salz davon zur Verwendung nach Anspruch 5, wobei die Darreichungsformen aus Tabletten, Kapseln, Granulat, Pillen, Pulvern, Paste, sublimierter Zubereitung, Pudern, Lösungen, Injektionen, Zäpfchen, Sprays, Tropfen, Pflastern und Weichkapseln ausgewählt sind.
  7. PEGylierter rekombinanter chimärer Human-Maus-Fibroblast-Wachstumsfaktor 21 oder pharmazeutisch annehmbares Salz davon zur Verwendung nach Anspruch 6, wobei die Darreichungsformen aus Pulverinjektionen oder Flüssiginj ektionen ausgewählt sind.
  8. PEGylierter rekombinanter chimärer Human-Maus-Fibroblast-Wachstumsfaktor 21 oder pharmazeutisch annehmbares Salz davon zur Verwendung nach Anspruch 7, wobei die Flüssiginjektionen aus Wasserinjektionen, Injektionen mit organischen Lösungsmitteln und Suspensionsinjektionen ausgewählt sind.
EP18771156.9A 2017-03-22 2018-03-19 Langwirkender mutanter humaner fibroblast-wachstumsfaktor 21 zur behandlung von nichtalkoholischer steatohepatitis Active EP3603660B1 (de)

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CN201710172824.0A CN108619490A (zh) 2017-03-22 2017-03-22 一种长效化突变的人源成纤维生长因子的新用途
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US20190367574A1 (en) 2019-12-05
JP7491839B2 (ja) 2024-05-28
RU2019125343A3 (de) 2021-03-31
RU2019125343A (ru) 2021-02-09
CN110520146A (zh) 2019-11-29
US20250042964A1 (en) 2025-02-06
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CA3049703A1 (en) 2018-09-27
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